Neoadjuvant immunotherapy for early-stage hepatocellular carcinoma: the arts and science

Since the introduction of immune checkpoint inhibitors (ICI) a few years ago, we have witnessed unprecedented improvement in survival in hepatocellular carcinoma (HCC). Advanced stage HCC now has a median overall survival (OS) of >1.5 years compared to just a little more than 6 months a decade ago. In contrast, survival of early-stage HCC has made little progress due to the lack of effective adjuvant strategy, as recurrence after curative treatment can reach up to 70% at 5 years. Given the success of immunotherapy in advanced stage HCC, there is a growing interest in incorporating immunotherapy in the management of early-stage HCC. Recently, the IMBRAVE050 trial reported positive outcomes showing, for the first time, the use of adjuvant immunotherapy (e.g. atezolizumab), plus bevacizumab, is effective in prolonging recurrence-free survival in early-stage HCC following curative treatment. On the other end of the spectrum, there is an increasing momentum to explore neoadjuvant immunotherapy for early-stage HCC. Preclinical models have shown that neoadjuvant immunotherapy can effectively stimulate a broader range of T cells that can translate into a stronger anti-tumour immune response when the tumour is left in situ. Neoadjuvant immunotherapy has also been shown to effectively improve pathological complete response rates and prolong survival in other cancer types. Under this context, several small-scale, early phase trials have demonstrated promising results using neoadjuvant immunotherapy in early-stage HCC. In this mini review, we will discuss the rationale behind, currently available data, and considerations of study design on evaluating neoadjuvant immunotherapy in early-stage HCC.